Reduced vagal tone in women with endometriosis and auricular vagus nerve stimulation as a potential therapeutic approach

Figures

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  Figure 1. Summary of heart rate variability (HRV) measurements between patients with ovarian endometriomas (OE) and healthy women (Controls). Total RMSSD (A), pNN50 (%) (B) and HF (C) are reduced significantly in patients with endometriosis as compared with controls. (D) The difference in LF did not reach statistical significance. (E) The mean LF/HF ratio is significantly higher in patients with endometriosis patient as compared with controls. (F) Scatter plot showing the relationship between HF and RMSSD, both log-transformed. Each red and blue dot represents one data point from patient with endometriosis and controls, respectively. The dashed line represents the regression line. The Pearson’s correlation coefficient is shown, along with its statistical significance level. Symbols for statistical significance levels: NS: p > 0.05; *p < 0.05; **p < 0.01; ***p < 0.001.

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  Figure 2. Vagotomy accelerates the development of endometriosis in mouse. (A) Kinetics of the mean bodyweight in the vagotomy and the control groups. No significance was found between two groups at any time point evaluated. (B) Kinetics of the average hotplate latency, tested at the indicated times in the two groups. Statistically significant difference in latency between the two groups is found at the end of the experiment, 2 weeks after the induction of endometriosis. (C) Boxplot of the lesion weight between mice with vagotomy and without. Representative immunostaining results for E-cadherin (D), vimentin (E) and α-SMA (F) in ectopic lesions from the two groups of mice (left panel), along the boxplot summarizing the immunostaining data (right panel). (G) Representative images of Masson trichrome staining in endometriotic lesions in vagotomy and control groups (left panel), along with the boxplot summarizing the results (right panel). The smooth muscle cells are stained in red and collagen fibers in blue. n = 10 in each group. The asterisk indicates the statistical significance level, calculated based on multiple linear regression analyses: NS: p > 0.05; *p < 0.05; **p < 0.01; ***p <…

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  Figure 3. Vagal nerve stimulation (VNS) decelerates the development of endometriosis in mouse. (A) Kinetics of the mean bodyweight in control and VNS groups. No significance was found between two groups at any time point evaluated. (B) Kinetics of the mean hotplate latency, tested at the indicated times in the two groups. Statistically significant difference in latency between the two groups is found at the end of the experiment, 2 weeks after the induction of endometriosis. (C) Boxplot summarizing the lesion weight data between control and VNS mice. Representative immunostaining results for E-cadherin (D) and vimentin (E) in endometriotic lesions from control and VNS mice (left panel), along the boxplot summarizing the staining data (right panel). (F) Representative images of Masson trichrome staining in endometriotic lesions in control and VNS groups (left panel), along with the boxplot summarizing the staining data (right panel). n = 10 in each group. The asterisk indicates the statistical significance level, based on linear regression using group indicator: NS: p > 0.05; *p < 0.05; **p < 0.01. The R2 values for E-cadherin and vimentin were 0.51 and 0.27, respectively. For the exent of…

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  Figure 4. Vagal nerve stimulation (VNS) demonstrates its therapeutic potentials in mouse with well-established endometriosis. (A) Kinetics of the mean bodyweight in VNS and the untreated groups. No significance was found between the two groups at any time point evaluated. (B) Kinetics of the mean hotplate latency, tested at the indicated time points, in the two groups. Statistically significant difference in latency between the two groups is found 2 weeks after the treatment with VNS. (C) Boxplot summarizing the lesion weight in the control and VNS groups. Representative immunostaining results for E-cadherin (D) and vimentin (E) in endometriotic lesions from untreated and VNS-treated mice (left panel), along the boxplot summarizing the staining data (right panel). (F) Representative images of Masson trichrome staining in endometriotic lesions in the two groups (left panel), along with the boxplot summarizing the staining data (right panel). The smooth muscle cells are stained in red and collagen fibers in blue. n = 10 in each group. The asterisk indicates the statistical significance level, which was calculated based on multiple linear regression analyses: NS: p > 0.05; *p < 0.05; **p <…

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  Figure 5. Illustrative diagram showing the possible intervention/therapeutic effects on endometriosis through the cholinergic anti-inflammatory pathway (CAIP). Endometriosis can induce pain and infertility, which can cause stress and depression, which, in turn, can lead to the activation of the HPA/SAM axes, resulting in increased release of catecholamines such as noradrenaline. The increased noradrenaline levels may induce the suppression of the DRD2 signaling pathway, the activation of the adrenergic receptor β2 (ADRB2), and the subsequent activation of the ADRB2/CREB/PKA signaling pathway, leading to increased angiogenesis and cellular proliferation, and thus lesional progression. Endometriotic lesions and inflammation are mutually stimulatory, and inflammation may also activate nociceptors such as TRPV1, facilitating pain sensation. The CAIP can be activated either by VNS or by α7nAChR agonists, leading to suppression, abrogation or attenuation of depression, pain, and inflammation, thereby achieving the therapeutic results.